Genetically engineered T lymphocytes have emerged as off-the-shelf serial killers capable of recognizing and eradicating solid and hematological cancers in vivo. T cells expressing chimeric antigen receptors (CARs) have the capacity of coupling MHC-unrestricted antibody-based antigen specificity with TCR-z and costimulatory signaling domains for antigen triggered T cell proliferation, engraftment and anti-tumor activity. Still, conventional gene therapy strategies developed for used in cell-based therapy for cancer are uniformly fixed in their antigen specificity, meaning only patients fortunat enough to have the prescribed antigen expressed on the surface of their cancer cells have the potential to experience meaningful benefit and may have limited efficacy in tumors with heterogeneous tumor-associated antigen expression. The cellular therapy field remains hindered by the inability to successfully develop the technology to deliver a flexible platform for the generation of highly personalized antigen-specific T cells with robust effector function and enhanced survival properties that can be widely applied for the treatment of the majority of patients with advanced disease. The capacity to develop a universal and flexible platform for the generation of non-MHC-restricted antigen-specific T cells has clear and significant clinical implications for adoptive immunotherapy of cancer and chronic viral infection. We build upon strong proof-of-concept results to test the central hypothesis that CAR-like therapy can be dramatically improved and widely applied to target multiple and diverse antigens either simultaneously or sequentially through innovative platform re-development. This extends upon NIH investment under the NIH R21 Exploratory/Developmental Bioengineering Research Grant mechanism, where the feasibility study scored in the 1% percentile and was noted for its innovative nature and strong potential for in vitro and clinical applications. Having now successfully established feasibility for universal immune receptors and identified opportunities for platform improvement, we are now well-positioned to extend these promising studies. Here, we unite scientific expertise in advanced antibody development and T cell-based gene engineering to propose 1) to optimize universal immune receptor construction for increased antibody intermediate binding; 2) to develop pre-therapeutic antibody-based imaging of TAA to combine with redirected T cell therapy as a predictor of potential for response; and 3) to improve anti-tumor efficacy in vivo through immune receptor re-development and improved tumor penetrance. Successful application of universal immune receptor platform as proposed here is staged to revolutionize CAR-like gene therapy through development of adaptable systems that allow for the first time flexibility in targeted antigen-specificity by redirected T cells and optiized T cell survival and function in vivo. PUBLIC HEALTH RELEVANCE: Innovative personalized approaches that broaden patient accessibility to T cell-based therapy are required to improve the control of advanced cancer and enhance health. In this study, we propose a pioneering approach to overcome the current limitations to engineered T cell therapy through the development of a universal system of T cell-based tumor targeting and killing. The public health benefit of this research will be the development of a highly personalized, tailor-made T cells based platform designed to broaden patient accessibility to effective T cell-based therapy of cancer.